Noninvasive, nuclear imaging techniques can be used to obtain basic and diagnostic information about the physiology and biochemistry of a variety of living subjects including experimental animals, normal humans and patients. These techniques rely on the use of sophisticated imaging instrumentation that is capable of detecting radiation emitted from radiotracers administered to such living subjects. The information obtained can be reconstructed to provide planar and tomographic images that reveal distribution of the radiotracer as a function of time. Use of appropriately designed radiotracers can result in images which contain information on the structure, function and most importantly, the physiology and biochemistry of the subject. Much of this information cannot be obtained by other means. The radiotracers used in these studies are designed to have defined behaviors in vivo which permit the determination of specific information concerning the physiology or biochemistry of the subject or the effects that various diseases or drugs have on the physiology or biochemistry of the subject. Currently, radiotracers are available for obtaining useful information concerning such things as cardiac function, myocardial blood flow, lung perfusion, liver function, brain blood flow, tumor imaging, regional brain glucose and oxygen metabolism.
Compounds can be labeled with either positron or gamma emitting radionuclides. For imaging, the most commonly used positron emitting (PET) radionuclides are 11C, 18F, 15O and 13N, all of which are accelerator produced, and have half lives of 20, 110, 2 and 10 minutes, respectively. Since the half-lives of these radionuclides are so short, it is only feasible to use them at institutions that have an accelerator on site or very close by for their production, thus limiting their use. Several gamma emitting radiotracers are available which can be used by essentially any hospital in the U.S. and in most hospitals worldwide. The most widely used of these are 99mTC, 201Tl and 123I.
In the last two decades, one of the most active areas of nuclear medicine research has been the development of receptor imaging radiotracers. These tracers bind with high affinity and specificity to selective receptors and neuroreceptors. Successful examples include radiotracers for imaging the following receptor or transporter systems: estrogen, muscarinic, serotonin, dopamine, opiate, neuropeptide-Y, cannabinoid-1 and neurokinin-1.
Alzheimer's disease is a progressive neurodegenerative disease characterized by the deposition of amyloid β protein (Aβ), accumulation of phosphorylated tau in a nerve cell (neurofibrillary tangle), and nerve cell death. In recent years, the number of patients with Alzheimer's disease is increasing because of aging, but an effective treatment method has not been developed as yet. The therapeutic drugs for Alzheimer's disease which are currently used in the medical practice are mainly acetylcholinesterase (AchE) inhibitors. While AchE inhibitors is confirmed to provide a certain level of usefulness, since they are used with the aim of supplementing decreased acetylcholine, the treatment with AchE inhibitor is merely a symptomatic therapy. Thus, the prompt development of a basic remedy and prophylactic drug has been strongly desired.
It has been clarified that the presence of allele ϵ4 of apolipoprotein E (ApoE) controlling the cholesterol metabolism is a strong risk factor of Alzheimer's disease (Science, vol. 261, 921-923, 1993). After this finding, the correlation between plural gene polymorphisms playing a role in the expression of protein controlling the cholesterol metabolism and the onset frequency of Alzheimer's disease has been shown, suggesting the correlation between the cholesterol metabolism and Alzheimer's disease (Neurobiol. Aging, vol. 24, 421-426, 2003; Mol. Psychiatry, vol. 8, 635-638, 2003). Moreover, it has been reported that a polymorphism in the gene of Cyp46 (same as “cholesterol 24-hydroxylase (CH24H)”), which is cholesterol oxidase specifically expressed in the brain, is a risk factor of Alzheimer's disease (Neurosci. Lett., vol. 328, pages 9-12, 2002). Furthermore, it has also been reported that Cyp46 (CH24H) is expressed in the vicinity of deposited amyloid in Alzheimer's disease patients (J. Biol. Chem., vol. 279, pages 34674-34681, 2004), 24S-hydroxycholesterol (24-HC), which is a metabolite thereof, increases in the brain spinal cord fluid (CSF) of Alzheimer's disease patients (Neurosci. Lett., vol. 324, pages 83-85, 2002; Neurosci. Lett., vol. 397, pages 83-87, 2006), 24-HC induces cell death of SH-SY5Y cell, which is a human neuroblast line (Brain Res., vol. 818, pages 171-175, 1999), and rats in which 24-HC was injected into the lateral cerebral ventricle showed impaired short-term memory, which is commonly observed in Alzheimer's disease, suggesting that hippocampal neurons were damaged by 24-HC (Neuroscience, vol. 164, pages 398-403, 2009). These findings suggest that Cyp46 (CH24H) is deeply involved in the pathology of Alzheimer's disease. Therefore, a compound that inhibits the Cyp46 (CH24H) activity (i.e., Cyp46 (CH24H) inhibitor) suppresses neuronal cell death, increase in Aβ, intracerebral inflammation and the like observed in Alzheimer's disease, by decreasing intracerebral 24-HC, and is promising as a therapeutic or prophylactic drug showing not only an improvement of symptoms but also a suppression of progression. Moreover, it has been reported that an AchE inhibitor clinically used as a therapeutic drug for Alzheimer's disease shows an improvement effect on memory disorders induced by Aβ in mouse (British Journal of Pharmacology, vol. 149, pages 998-1012, 2006). Thus, a Cyp46 (CH24H) inhibitor is promising as a new therapeutic or prophylactic drug for Alzheimer's disease.
As a concept of the preclinical stage of Alzheimer's disease, a mild cognitive impairment has been proposed, and about half of those having this disorder is said to progress into the Alzheimer's disease in the future. In recent years, it has been reported that 24-HC increases not only in patients with Alzheimer's disease but also in CSF of patients with mild cognitive impairment (Neurosci. Lett., vol. 397, pages 83-87, 2006). This finding suggests that Cyp46 (CH24H) is involved in the pathology of mild cognitive impairment, and therefore, a Cyp46 (CH24H) inhibitor is promising as a new therapeutic drug for Alzheimer's disease or a prophylactic drug for the progression into the Alzheimer's disease.
In recent years, moreover, it has been reported that 24-HC in the blood increases before expression of the symptom in an autoimmune encephalomyelitis model, which is an animal model of multiple sclerosis which is one of the demyelination diseases in the central nervous system (J. Neurosci. Res., vol. 85, pages 1499-1505, 2007). Multiple sclerosis is often developed in younger people of about 30 years old, and scarcely developed in the elderly of 60 years or older. It has also been reported that 24-HC in the blood increases in multiple sclerosis patients aged from 21 to 50 (Neurosci. Lett., vol. 331, pages 163-166, 2002). These findings suggest that Cyp46 (CH24H) is involved in the pathology of multiple sclerosis, and therefore, a Cyp46 (CH24H) inhibitor is promising as a new therapeutic or prophylactic drug for multiple sclerosis.
Traumatic brain injury (also referred to as TBI in the present specification) is a condition having an extremely harmful influence on the personal health, for which no effective cure has been established. In the repair process following tissue damage by TBI, reconstruction of neuronal cell membrane and distribution of intracerebral cholesterol along with the growth of glial cell are suggested to be activated (Proc. Natl. Acad. Sci. USA, vol. 102, pages 8333-8338, 2005). In a rat TBI model, an enhanced expression of Cyp46 (CH24H) after trauma has been reported (J. Neurotrauma, vol. 25, pages 1087-1098, 2008). Moreover, it has also been reported that 24-HC is injurious to neuronal cells (Brain Res., vol. 818, pages 171-175, 1999). Therefore, a Cyp46 (CH24H) inhibitor is promising as a new therapeutic or prophylactic drug for TBI.
As a pathological significance of 24-HC in neurodegenerative diseases, an inflammatory gene expression-enhancing action in neuronal cells has been reported (NeuroReport, vol. 16, pages 909-913, 2005). In addition, it is suggested that an intracerebral inflammation reaction accompanied by activation of glial cell is a pathological change characteristic of neurodegenerative diseases (Glia, vol. 50, pages 427-434, 2005). In recent years, an effectiveness of therapy by suppression of intracerebral inflammation has also been reported for neurodegenerative diseases such as Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis and the like (Mol. Neurodegeneration, vol. 4, pages 47-59, 2009). Furthermore, 24-HC has recently been suggested to be an endogenous activator of the N-methyl-d-aspartate (NMDA) receptor, whose over-activation is thought play a key role in the glutamate toxicity (J. Neurosci., vol. 33, pages 17290-17300, 2013). Therefore, with a mechanism to regulate intracerebral inflammation and/or glutamatergic transmission, pharmacological reduction of 24-HC by the inhibition of Cyp46 (CH24H) is promising as a new therapeutic or prophylactic drug for neurological diseases such as Huntington's disease, Parkinson's disease, cerebral infarction, glaucoma, amyotrophic lateral sclerosis, epilepsy syndromes and the like.
Glaucoma is the main cause of blindness, and is considered to be a serious social problem. However, there is no effective cure of a normal intraocular pressure type-visual field constriction, which is the major symptom of the disease. In recent years, it has been reported that gene polymorphisms of Cyp46 (CH24H) associated with high value of 24-HC in blood is related to the risk of the onset of glaucoma (Invest. Ophthalmol. Vis. Sci., vol. 50, pages 5712-5717, 2009). Thus, a Cyp46 (CH24H) inhibitor is promising as a therapeutic or prophylactic drug for glaucoma.
Seizure is a disorder that convulsively occurs with abnormal electrical excitation of neuronal cell in the brain. Seizure is one of the characteristic clinical findings of Alzheimer's disease (Epilepsia, vol. 47, pages 867-872, 2006), and the relationship between epilepsy and onset of Alzheimer's disease has been indicated (Epilepsia, vol. 52, Supplement 1, pages 39-46, 2011). It has been reported that seizure occurs with high frequency in APP/PS1 double transgenic mouse which is one of the Alzheimer's disease models due to Aβ overexpression (J. Neurosci., vol. 29, pages 3453-3462, 2012). Furthermore, since hippocampus astrocytes induce the expression of Cyp46 (CH24H) in a kainic acid lesion rat model, which is one of the epilepsy models, the relationship between this enzyme and pathology of epilepsy has been indicated (J. Neurol., vol. 65, pages 652-663, 2006). It has been reported that a therapeutic drug for seizure, carbamazepine, shows an improving effect on short-term memory in Y-maze test in an epileptic spasm mouse model (J. Neurol. Neurosurg. Psychiatry, vol. 48, pages 459-468, 1985). Therefore, a CH24H inhibitor, which shows an improving effect on short-term memory in a model animal showing an epileptic symptom, is promising as a novel therapeutic drug or prophylaxis drug for spasm, epilepsy, and the like.
Since schizophrenia shows a variety of psychological symptoms such as hallucination, delusion, excitation, manic-depressive state and the like, therapeutic drugs therefor have been developed with various approaches. In recent years, it has been pointed out that changes in the cholesterol metabolism are involved in the abnormality of neural activity seen in schizophrenia (J. Psychiatry Neurosci., vol. 36, pages 47-55, 2011). Since cytotoxic factors such as oxidative stress also contribute to the pathology of schizophrenia, neuronal cell toxicity of 24-HC may aggravate the symptoms (Psychoneuroendocrinology, vol. 28, pages 83-96, 2003). Therefore, a Cyp46 (CH24H) inhibitor that inhibits metabolizing cholesterol to 24-HC in the brain is promising as a therapeutic or prophylactic drug for schizophrenia.
Striatum (caudate, putamen) is reportedly a brain region high in the level of CH24H protein expression in primates in comparison with the globus pallidus, brainstem and cerebellum (Neurosci Bull., vol. 26, pages 197-204, 2010).
Neurodegenerative diseases such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and Alzheimer's disease are related to dysfunction in striatum (Neuroimaging Clin. N. Am., vol. 22, pages 57-65, 2012; Can. J. Neurol. Sci. vol 13, pages 546-558, 1986; Acta. Neurol. Scand. Suppl., vol. 51, pages 139-150, 1972; Ann. Neurol., vol. 74, pages 20-38, 2013). Psychiatric disorders such as depression, schizophrenia and anxiety disorders, and other neurological disorders as epilepsy, ischemia and stroke are also related to these area (Dis. Nerv. Syst., vol. 33, pages 711-719, 1972; Dev. Cogn. Neurosci., vol. 8, pages 65-76, 2014; PLoS. One., vol. 8 pages e69905, 2013)
Under pathological condition, glial induction of CH24H was detected by means of immunohistochemistry with CH24H-specific antibody in Alzheimer's disease and traumatic brain injury (J. Biol. Chem., vol. 279, pages 34674-34681, 2004; Neurosci. Lett., vol. 314, pages 45-48, 2001); Histochem. Cell Biol., vol. 134, pages 159-169, 2010). These studies indicate the importance of on-site detection of CH24H by a methodology like histology or tomography. Experimental kainite-induced excitotoxicity also induced its expression in astrocytes in parallel with the increased 24-HC levels (J. Neuropathol. Exp. Neurol., vol. 65, pages 652-663, 2006). In contrast to the neuronal expression, the glial expression of CH24H is thought to be pathological response (Brain Res., vol. 818, pages 171-175, 1999). Therefore, CH24H could possibly play a role in brain diseases which are accompanied by glial activation such as epilepsy, glaucoma, multiple sclerosis, neuropathic pain, traumatic brain injury, spinal cord injury, migraine, stroke, Parkinson's disease, Huntington disease amyotrophic lateral sclerosis and detection of altered CH24H expression could lead to a diagnostic application for these diseases by such means as histological, radiological or biochemical analyses.
PET (Positron Emission Tomography) radiotracers and imaging technology may provide a powerful method for clinical evaluation and dose selection of CH24H inhibitors, and for diagnostic imaging with respect to any of the disorders associated with CH24H, such as epilepsy, neurodegenerative disease (e.g., Alzheimer's disease, mild cognitive disorder, Huntington's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, glaucoma and the like), schizophrenia and the like. Thus, the invention herein is directed to radiolabeled CH24H inhibitors that would be useful for exploratory and diagnostic imaging applications, both in vitro and in vivo, and for competition studies using radiolabeled and unlabeled CH24H inhibitors.
As a CH24H inhibitor, the following compounds have been known.
Patent Document 1 discloses the following compound:
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Patent Document 2 discloses the following compound:
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Patent Document 3 discloses the following compound:
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Patent Document 4 discloses the following compound:
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Patent Document 5 discloses the following compound:
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Patent Document 6 discloses the following compound:
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None of these documents do not disclose nor teach that the radiolabeled compound of the present invention is useful as a PET radiotracer.